{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T02:32:51Z","timestamp":1775788371494,"version":"3.50.1"},"reference-count":147,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["5T32 AI007319-33"],"award-info":[{"award-number":["5T32 AI007319-33"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["T32 T32NS121727"],"award-info":[{"award-number":["T32 T32NS121727"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["P30AG066519"],"award-info":[{"award-number":["P30AG066519"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["RO1AG056850"],"award-info":[{"award-number":["RO1AG056850"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["RO1AG056850"],"award-info":[{"award-number":["RO1AG056850"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["RO1AG056850"],"award-info":[{"award-number":["RO1AG056850"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"crossref","award":["RO1AG056850"],"award-info":[{"award-number":["RO1AG056850"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 AG000096"],"award-info":[{"award-number":["T32 AG000096"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["INT21\/00073"],"award-info":[{"award-number":["INT21\/00073"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Horizon 2020\u2013Research and Innovation Framework Programme from the European Union","award":["H2020-SC1-BHC-2018-2020"],"award-info":[{"award-number":["H2020-SC1-BHC-2018-2020"]}]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades","award":["IIBSP-DOW-2020-151"],"award-info":[{"award-number":["IIBSP-DOW-2020-151"]}]},{"name":"ALZ Discovery grant from the Alzheimer\u2019s Association","award":["1051950"],"award-info":[{"award-number":["1051950"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Neuropathol"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Individuals with Down Syndrome (DS) represent one of the most susceptible populations for developing severe COVID-19, and a unique human genetic condition for investigating molecular mechanisms underlying susceptibility of neurologically vulnerable individuals to SARS-CoV-2 infection. Human Chromosome-21 (HSA21) triplication in DS causes global transcriptional deregulation, affecting multiple genes that may directly (e.g., TMPRSS2) or indirectly influence the SARS-CoV-2 entry into central nervous system (CNS) cells. The anti-viral immune response may also be altered in cells with trisomy-21 (T21) due to triplication of genes encoding for several interferon receptor subunits and interferon-stimulated genes (ISGs). Here, we demonstrate that human cells derived from fetal cortical specimens and maintained in primary cultures are susceptible to infection with a molecular clone of vesicular stomatitis virus engineered to express the Spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and to authentic SARS-CoV-2. The level of SARS-CoV-2 infectivity in cultures originated from different cortical specimens varied, seemingly depending on ploidy and chromosomal sex of the cells. We confirmed the presence of ACE2 and TMPRSS2 in cultures and found that XY T21 group had the highest TMPRSS2 mRNA levels, which was associated with increased infectivity in XY\u2014compared to XX T21 cultures. The XX T21 cultures exhibited elevated expression of several ISGs (MX1, STAT1, and STAT2) which was associated with lower infectivity. The comparisons of postmortem aged brain specimens revealed reduced ACE2, TMPRSS2, but elevated STAT2 protein levels in individuals with DS and Alzheimer\u2019s disease (DS-AD) compared to control and Alzheimer\u2019s disease (AD) group. Collectively, these results suggest multifactorial regulation of SARS-CoV-2 infectivity in cortical cells that involves ploidy, chromosomal sex, and the expression of genes implicated in regulation of virus entry and anti-viral response as contributing factors.<\/jats:p>","DOI":"10.1007\/s00401-025-02895-2","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T05:17:40Z","timestamp":1748582260000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SARS-CoV-2 infection of human cortical cells is influenced by the interaction between aneuploidy and biological sex: insights from a Down syndrome in vitro model"],"prefix":"10.1007","volume":"149","author":[{"given":"Maria I.","family":"Lioudyno","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evgueni A.","family":"Sevrioukov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gema M.","family":"Olivarria","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Hitchcock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominic I.","family":"Javonillo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sydney M.","family":"Campos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sierra T.","family":"Wright","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Head","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Fortea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Wisniewski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. Claudio","family":"Cuello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Do Carmo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas E.","family":"Lane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Busciglio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"key":"2895_CR1","doi-asserted-by":"publisher","unstructured":"Ahmed W, Feng J, Zhang Y, Chen L (2023) SARS-CoV-2 and brain health: new challenges in the era of the pandemic. Microorganisms 11. https:\/\/doi.org\/10.3390\/microorganisms11102511","DOI":"10.3390\/microorganisms11102511"},{"key":"2895_CR2","doi-asserted-by":"publisher","unstructured":"Alldred MJ, Martini AC, Patterson D, Hendrix J, Granholm AC (2021) Aging with down syndrome-where are we now and where are we going? J Clin Med 10. https:\/\/doi.org\/10.3390\/jcm10204687","DOI":"10.3390\/jcm10204687"},{"key":"2895_CR3","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1158\/1535-7163.MCT-12-0923","volume":"12","author":"J Amalraj","year":"2013","unstructured":"Amalraj J, Cutler SJ, Ghazawi I, Boyle GM, Ralph SJ (2013) REST negatively and ISGF3 positively regulate the human STAT1 gene in melanoma. Mol Cancer Ther 12:1288\u20131298. https:\/\/doi.org\/10.1158\/1535-7163.MCT-12-0923","journal-title":"Mol Cancer Ther"},{"key":"2895_CR4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000582","volume":"5","author":"V Avadhanula","year":"2009","unstructured":"Avadhanula V, Weasner BP, Hardy GG, Kumar JP, Hardy RW (2009) A novel system for the launch of alphavirus RNA synthesis reveals a role for the Imd pathway in arthropod antiviral response. PLoS Pathog 5:e1000582. https:\/\/doi.org\/10.1371\/journal.ppat.1000582","journal-title":"PLoS Pathog"},{"key":"2895_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100306","volume":"296","author":"A Bayati","year":"2021","unstructured":"Bayati A, Kumar R, Francis V, McPherson PS (2021) SARS-CoV-2 infects cells after viral entry via clathrin-mediated endocytosis. J Biol Chem 296:100306. https:\/\/doi.org\/10.1016\/j.jbc.2021.100306","journal-title":"J Biol Chem"},{"key":"2895_CR6","doi-asserted-by":"publisher","unstructured":"Bestle D, Heindl MR, Limburg H, Van Lam van T, Pilgram O, Moulton H, Stein DA, Hardes K, Eickmann M, Dolnik Oet al (2020) TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Sci Alliance 3. https:\/\/doi.org\/10.26508\/lsa.202000786","DOI":"10.26508\/lsa.202000786"},{"key":"2895_CR7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167265","volume":"434","author":"DK Beyer","year":"2022","unstructured":"Beyer DK, Forero A (2022) Mechanisms of antiviral immune evasion of SARS-CoV-2. J Mol Biol 434:167265. https:\/\/doi.org\/10.1016\/j.jmb.2021.167265","journal-title":"J Mol Biol"},{"key":"2895_CR8","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1021\/acschemneuro.0c00210","volume":"11","author":"K Bilinska","year":"2020","unstructured":"Bilinska K, Jakubowska P, Von Bartheld CS, Butowt R (2020) Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in cells of the olfactory epithelium: identification of cell types and trends with age. ACS Chem Neurosci 11:1555\u20131562. https:\/\/doi.org\/10.1021\/acschemneuro.0c00210","journal-title":"ACS Chem Neurosci"},{"key":"2895_CR9","doi-asserted-by":"publisher","unstructured":"Bloise E, Zhang J, Nakpu J, Hamada H, Dunk CE, Li S, Imperio GE, Nadeem L, Kibschull M, Lye Pet al (2021) Expression of severe acute respiratory syndrome coronavirus 2 cell entry genes, angiotensin-converting enzyme 2 and transmembrane protease serine 2, in the placenta across gestation and at the maternal-fetal interface in pregnancies complicated by preterm birth or preeclampsia. Am J Obstet Gynecol 224:298 e291\u2013298 e298. https:\/\/doi.org\/10.1016\/j.ajog.2020.08.055","DOI":"10.1016\/j.ajog.2020.08.055"},{"key":"2895_CR10","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/s41588-020-00759-x","volume":"53","author":"C Blume","year":"2021","unstructured":"Blume C, Jackson CL, Spalluto CM, Legebeke J, Nazlamova L, Conforti F et al (2021) A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection. Nat Genet 53:205\u2013214. https:\/\/doi.org\/10.1038\/s41588-020-00759-x","journal-title":"Nat Genet"},{"key":"2895_CR11","doi-asserted-by":"publisher","first-page":"8887","DOI":"10.1128\/JVI.00415-08","volume":"82","author":"BJ Bosch","year":"2008","unstructured":"Bosch BJ, Bartelink W, Rottier PJ (2008) Cathepsin L functionally cleaves the severe acute respiratory syndrome coronavirus class I fusion protein upstream of rather than adjacent to the fusion peptide. J Virol 82:8887\u20138890. https:\/\/doi.org\/10.1128\/JVI.00415-08","journal-title":"J Virol"},{"key":"2895_CR12","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","volume":"82","author":"H Braak","year":"1991","unstructured":"Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239\u2013259. https:\/\/doi.org\/10.1007\/BF00308809","journal-title":"Acta Neuropathol"},{"key":"2895_CR13","doi-asserted-by":"publisher","first-page":"678","DOI":"10.23736\/S0375-9393.20.14772-2","volume":"86","author":"G Bulfamante","year":"2020","unstructured":"Bulfamante G, Chiumello D, Canevini MP, Priori A, Mazzanti M, Centanni S et al (2020) First ultrastructural autoptic findings of SARS -Cov-2 in olfactory pathways and brainstem. Minerva Anestesiol 86:678\u2013679. https:\/\/doi.org\/10.23736\/S0375-9393.20.14772-2","journal-title":"Minerva Anestesiol"},{"key":"2895_CR14","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.1056\/NEJMra1706537","volume":"382","author":"MJ Bull","year":"2020","unstructured":"Bull MJ (2020) Down syndrome. N Engl J Med 382:2344\u20132352. https:\/\/doi.org\/10.1056\/NEJMra1706537","journal-title":"N Engl J Med"},{"key":"2895_CR15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004502","volume":"10","author":"C Burkard","year":"2014","unstructured":"Burkard C, Verheije MH, Wicht O, van Kasteren SI, van Kuppeveld FJ, Haagmans BL et al (2014) Coronavirus cell entry occurs through the endo-\/lysosomal pathway in a proteolysis-dependent manner. PLoS Pathog 10:e1004502. https:\/\/doi.org\/10.1371\/journal.ppat.1004502","journal-title":"PLoS Pathog"},{"key":"2895_CR16","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.bbi.2020.12.031","volume":"95","author":"SM Burks","year":"2021","unstructured":"Burks SM, Rosas-Hernandez H, Alejandro Ramirez-Lee M, Cuevas E, Talpos JC (2021) Can SARS-CoV-2 infect the central nervous system via the olfactory bulb or the blood-brain barrier? Brain Behav Immun 95:7\u201314. https:\/\/doi.org\/10.1016\/j.bbi.2020.12.031","journal-title":"Brain Behav Immun"},{"key":"2895_CR17","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/0896-6273(95)90232-5","volume":"14","author":"J Busciglio","year":"1995","unstructured":"Busciglio J, Lorenzo A, Yeh J, Yankner BA (1995) Beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14:879\u2013888. https:\/\/doi.org\/10.1016\/0896-6273(95)90232-5","journal-title":"Neuron"},{"key":"2895_CR18","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/s0896-6273(02)00604-9","volume":"33","author":"J Busciglio","year":"2002","unstructured":"Busciglio J, Pelsman A, Wong C, Pigino G, Yuan M, Mori H et al (2002) Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down\u2019s syndrome. Neuron 33:677\u2013688. https:\/\/doi.org\/10.1016\/s0896-6273(02)00604-9","journal-title":"Neuron"},{"key":"2895_CR19","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1038\/378776a0","volume":"378","author":"J Busciglio","year":"1995","unstructured":"Busciglio J, Yankner BA (1995) Apoptosis and increased generation of reactive oxygen species in down\u2019s syndrome neurons in vitro. Nature 378:776\u2013779. https:\/\/doi.org\/10.1038\/378776a0","journal-title":"Nature"},{"key":"2895_CR20","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1111\/j.1471-4159.1993.tb13658.x","volume":"61","author":"J Busciglio","year":"1993","unstructured":"Busciglio J, Yeh J, Yankner BA (1993) beta-Amyloid neurotoxicity in human cortical culture is not mediated by excitotoxins. J Neurochem 61:1565\u20131568. https:\/\/doi.org\/10.1111\/j.1471-4159.1993.tb13658.x","journal-title":"J Neurochem"},{"key":"2895_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2021.577728","volume":"361","author":"VF Cama","year":"2021","unstructured":"Cama VF, Marin-Prida J, Acosta-Rivero N, Acosta EF, Diaz LO, Casadesus AV et al (2021) The microglial NLRP3 inflammasome is involved in human SARS-CoV-2 cerebral pathogenicity: a report of three post-mortem cases. J Neuroimmunol 361:577728. https:\/\/doi.org\/10.1016\/j.jneuroim.2021.577728","journal-title":"J Neuroimmunol"},{"key":"2895_CR22","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1126\/science.abd2985","volume":"370","author":"L Cantuti-Castelvetri","year":"2020","unstructured":"Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S et al (2020) Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 370:856\u2013860. https:\/\/doi.org\/10.1126\/science.abd2985","journal-title":"Science"},{"key":"2895_CR23","doi-asserted-by":"publisher","first-page":"S5","DOI":"10.1016\/j.neurop.2021.07.005","volume":"1","author":"FJ Carod-Artal","year":"2021","unstructured":"Carod-Artal FJ, Garcia-Monco JC (2021) Epidemiology, pathophysiology, and classification of the neurological symptoms of post-COVID-19 syndrome. Neurol Perspect 1:S5\u2013S15. https:\/\/doi.org\/10.1016\/j.neurop.2021.07.005","journal-title":"Neurol Perspect"},{"key":"2895_CR24","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1136\/bjophthalmol-2020-318618","volume":"106","author":"M Casagrande","year":"2022","unstructured":"Casagrande M, Fitzek A, Spitzer M, Puschel K, Glatzel M, Krasemann S et al (2022) Detection of SARS-CoV-2 genomic and subgenomic RNA in retina and optic nerve of patients with COVID-19. Br J Ophthalmol 106:1313\u20131317. https:\/\/doi.org\/10.1136\/bjophthalmol-2020-318618","journal-title":"Br J Ophthalmol"},{"issue":"475\u2013485","key":"2895_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.06.021","volume":"28","author":"JB Case","year":"2020","unstructured":"Case JB, Rothlauf PW, Chen RE, Liu Z, Zhao H, Kim AS et al (2020) Neutralizing antibody and soluble ACE2 inhibition of a replication-competent VSV-SARS-CoV-2 and a clinical isolate of SARS-CoV-2. Cell Host Microbe 28(475\u2013485):e475. https:\/\/doi.org\/10.1016\/j.chom.2020.06.021","journal-title":"Cell Host Microbe"},{"key":"2895_CR26","doi-asserted-by":"publisher","first-page":"10078","DOI":"10.1074\/jbc.M109.034793","volume":"285","author":"S Ceru","year":"2010","unstructured":"Ceru S, Konjar S, Maher K, Repnik U, Krizaj I, Bencina M et al (2010) Stefin B interacts with histones and cathepsin L in the nucleus. J Biol Chem 285:10078\u201310086. https:\/\/doi.org\/10.1074\/jbc.M109.034793","journal-title":"J Biol Chem"},{"key":"2895_CR27","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00862-21","volume":"95","author":"DY Chen","year":"2021","unstructured":"Chen DY, Khan N, Close BJ, Goel RK, Blum B, Tavares AH et al (2021) SARS-CoV-2 disrupts proximal elements in the JAK-STAT pathway. J Virol 95:e0086221. https:\/\/doi.org\/10.1128\/JVI.00862-21","journal-title":"J Virol"},{"key":"2895_CR28","doi-asserted-by":"publisher","first-page":"5187","DOI":"10.2147\/JIR.S280953","volume":"14","author":"H Chung","year":"2021","unstructured":"Chung H, Green PHR, Wang TC, Kong XF (2021) Interferon-driven immune dysregulation in down syndrome: a review of the evidence. J Inflamm Res 14:5187\u20135200. https:\/\/doi.org\/10.2147\/JIR.S280953","journal-title":"J Inflamm Res"},{"key":"2895_CR29","doi-asserted-by":"publisher","first-page":"572","DOI":"10.7326\/M20-4986","volume":"174","author":"AK Clift","year":"2021","unstructured":"Clift AK, Coupland CAC, Keogh RH, Hemingway H, Hippisley-Cox J (2021) COVID-19 mortality risk in down syndrome: results from a cohort study of 8 million adults. Ann Intern Med 174:572\u2013576. https:\/\/doi.org\/10.7326\/M20-4986","journal-title":"Ann Intern Med"},{"key":"2895_CR30","doi-asserted-by":"publisher","first-page":"3856","DOI":"10.1111\/ene.15045","volume":"28","author":"G Cosentino","year":"2021","unstructured":"Cosentino G, Todisco M, Hota N, Della Porta G, Morbini P, Tassorelli C et al (2021) Neuropathological findings from COVID-19 patients with neurological symptoms argue against a direct brain invasion of SARS-CoV-2: a critical systematic review. Eur J Neurol 28:3856\u20133865. https:\/\/doi.org\/10.1111\/ene.15045","journal-title":"Eur J Neurol"},{"key":"2895_CR31","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.684874","volume":"9","author":"H Cui","year":"2021","unstructured":"Cui H, Su S, Cao Y, Ma C, Qiu W (2021) The altered anatomical distribution of ACE2 in the brain with Alzheimer\u2019s disease pathology. Front Cell Dev Biol 9:684874. https:\/\/doi.org\/10.3389\/fcell.2021.684874","journal-title":"Front Cell Dev Biol"},{"key":"2895_CR32","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/s0140-6736(94)90815-x","volume":"343","author":"KH Cui","year":"1994","unstructured":"Cui KH, Warnes GM, Jeffrey R, Matthews CD (1994) Sex determination of preimplantation embryos by human testis-determining-gene amplification. Lancet 343:79\u201382. https:\/\/doi.org\/10.1016\/s0140-6736(94)90815-x","journal-title":"Lancet"},{"key":"2895_CR33","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105418","volume":"156","author":"E Daura","year":"2021","unstructured":"Daura E, Tegelberg S, Yoshihara M, Jackson C, Simonetti F, Aksentjeff K et al (2021) Cystatin B-deficiency triggers ectopic histone H3 tail cleavage during neurogenesis. Neurobiol Dis 156:105418. https:\/\/doi.org\/10.1016\/j.nbd.2021.105418","journal-title":"Neurobiol Dis"},{"key":"2895_CR34","doi-asserted-by":"publisher","first-page":"4235898","DOI":"10.1155\/2016\/4235898","volume":"2016","author":"I De Toma","year":"2016","unstructured":"De Toma I, Manubens-Gil L, Ossowski S, Dierssen M (2016) Where environment meets cognition: a focus on two developmental intellectual disability disorders. Neural Plast 2016:4235898. https:\/\/doi.org\/10.1155\/2016\/4235898","journal-title":"Neural Plast"},{"key":"2895_CR35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1009317","volume":"17","author":"I De Toma","year":"2021","unstructured":"De Toma I, Sierra C, Dierssen M (2021) Meta-analysis of transcriptomic data reveals clusters of consistently deregulated gene and disease ontologies in down syndrome. PLoS Comput Biol 17:e1009317. https:\/\/doi.org\/10.1371\/journal.pcbi.1009317","journal-title":"PLoS Comput Biol"},{"key":"2895_CR36","doi-asserted-by":"publisher","unstructured":"Deinhardt-Emmer S, Wittschieber D, Sanft J, Kleemann S, Elschner S, Haupt KF, Vau V, Haring C, Rodel J, Henke A et al (2021) Early postmortem mapping of SARS-CoV-2 RNA in patients with COVID-19 and the correlation with tissue damage. Elife 10. https:\/\/doi.org\/10.7554\/eLife.60361","DOI":"10.7554\/eLife.60361"},{"key":"2895_CR37","doi-asserted-by":"publisher","first-page":"6011","DOI":"10.1523\/JNEUROSCI.1189-06.2006","volume":"26","author":"A Deshpande","year":"2006","unstructured":"Deshpande A, Mina E, Glabe C, Busciglio J (2006) Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J Neurosci 26:6011\u20136018. https:\/\/doi.org\/10.1523\/JNEUROSCI.1189-06.2006","journal-title":"J Neurosci"},{"key":"2895_CR38","doi-asserted-by":"publisher","first-page":"2357","DOI":"10.1096\/fj.07-096909","volume":"22","author":"A Deshpande","year":"2008","unstructured":"Deshpande A, Win KM, Busciglio J (2008) Tau isoform expression and regulation in human cortical neurons. FASEB J 22:2357\u20132367. https:\/\/doi.org\/10.1096\/fj.07-096909","journal-title":"FASEB J"},{"key":"2895_CR39","doi-asserted-by":"publisher","unstructured":"Ding Q, Shults NV, Gychka SG, Harris BT, Suzuki YJ (2021) Protein expression of angiotensin-converting enzyme 2 (ACE2) is upregulated in brains with Alzheimer\u2019s disease. Int J Mol Sci 22. https:\/\/doi.org\/10.3390\/ijms22041687","DOI":"10.3390\/ijms22041687"},{"key":"2895_CR40","doi-asserted-by":"publisher","first-page":"459","DOI":"10.3233\/JAD-160836","volume":"56","author":"E Doran","year":"2017","unstructured":"Doran E, Keator D, Head E, Phelan MJ, Kim R, Totoiu M et al (2017) Down syndrome, partial trisomy 21, and absence of Alzheimer\u2019s disease: the role of APP. J Alzheimers Dis 56:459\u2013470. https:\/\/doi.org\/10.3233\/JAD-160836","journal-title":"J Alzheimers Dis"},{"key":"2895_CR41","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1038\/s41586-022-04569-5","volume":"604","author":"G Douaud","year":"2022","unstructured":"Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P et al (2022) SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 604:697\u2013707. https:\/\/doi.org\/10.1038\/s41586-022-04569-5","journal-title":"Nature"},{"key":"2895_CR42","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.wneu.2020.05.194","volume":"140","author":"IE Efe","year":"2020","unstructured":"Efe IE, Aydin OU, Alabulut A, Celik O, Aydin K (2020) COVID-19-associated encephalitis mimicking glial tumor. World Neurosurg 140:46\u201348. https:\/\/doi.org\/10.1016\/j.wneu.2020.05.194","journal-title":"World Neurosurg"},{"key":"2895_CR43","doi-asserted-by":"publisher","first-page":"1039427","DOI":"10.3389\/fimmu.2022.1039427","volume":"13","author":"JP Elizalde-Diaz","year":"2022","unstructured":"Elizalde-Diaz JP, Miranda-Narvaez CL, Martinez-Lazcano JC, Martinez-Martinez E (2022) The relationship between chronic immune response and neurodegenerative damage in long COVID-19. Front Immunol 13:1039427. https:\/\/doi.org\/10.3389\/fimmu.2022.1039427","journal-title":"Front Immunol"},{"key":"2895_CR44","doi-asserted-by":"publisher","unstructured":"Emes D, Huls A, Baumer N, Dierssen M, Puri S, Russell L, Sherman SL, Strydom A, Bargagna S, Brandao ACet al (2021) COVID-19 in children with down syndrome: data from the trisomy 21 research society survey. J Clin Med 10. https:\/\/doi.org\/10.3390\/jcm10215125","DOI":"10.3390\/jcm10215125"},{"key":"2895_CR45","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/s41531-023-00467-3","volume":"9","author":"A Emmi","year":"2023","unstructured":"Emmi A, Rizzo S, Barzon L, Sandre M, Carturan E, Sinigaglia A et al (2023) Detection of SARS-CoV-2 viral proteins and genomic sequences in human brainstem nuclei. NPJ Parkinsons Dis 9:25. https:\/\/doi.org\/10.1038\/s41531-023-00467-3","journal-title":"NPJ Parkinsons Dis"},{"key":"2895_CR46","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/S0074-7750(10)39004-5","volume":"39","author":"AJ Esbensen","year":"2010","unstructured":"Esbensen AJ (2010) Health conditions associated with aging and end of life of adults with down syndrome. Int Rev Res Ment Retard 39:107\u2013126. https:\/\/doi.org\/10.1016\/S0074-7750(10)39004-5","journal-title":"Int Rev Res Ment Retard"},{"key":"2895_CR47","doi-asserted-by":"publisher","unstructured":"Finlay JB, Brann DH, Abi Hachem R, Jang DW, Oliva AD, Ko T, Gupta R, Wellford SA, Moseman EA, Jang SSet al (2022) Persistent post-COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium. Sci Transl Med 14:eadd0484. https:\/\/doi.org\/10.1126\/scitranslmed.add0484","DOI":"10.1126\/scitranslmed.add0484"},{"key":"2895_CR48","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1016\/S0140-6736(20)30689-9","volume":"395","author":"J Fortea","year":"2020","unstructured":"Fortea J, Vilaplana E, Carmona-Iragui M, Benejam B, Videla L, Barroeta I et al (2020) Clinical and biomarker changes of Alzheimer\u2019s disease in adults with down syndrome: a cross-sectional study. Lancet 395:1988\u20131997","journal-title":"Lancet"},{"key":"2895_CR49","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1016\/S1474-4422(21)00245-3","volume":"20","author":"J Fortea","year":"2021","unstructured":"Fortea J, Zaman SH, Hartley S, Rafii MS, Head E, Carmona-Iragui M (2021) Alzheimer\u2019s disease associated with down syndrome: a genetic form of dementia. The Lancet Neurology 20:930\u2013942. https:\/\/doi.org\/10.1016\/S1474-4422(21)00245-3","journal-title":"The Lancet Neurology"},{"key":"2895_CR50","doi-asserted-by":"publisher","unstructured":"Galbraith MD, Rachubinski AL, Smith KP, Araya P, Waugh KA, Enriquez-Estrada B, Worek K, Granrath RE, Kinning KT, Paul Eduthan Net al (2023) Multidimensional definition of the interferonopathy of down syndrome and its response to JAK inhibition. Sci Adv 9:eadg6218. https:\/\/doi.org\/10.1126\/sciadv.adg6218","DOI":"10.1126\/sciadv.adg6218"},{"key":"2895_CR51","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101615","volume":"36","author":"E Gkogkou","year":"2020","unstructured":"Gkogkou E, Barnasas G, Vougas K, Trougakos IP (2020) Expression profiling meta-analysis of ACE2 and TMPRSS2, the putative anti-inflammatory receptor and priming protease of SARS-CoV-2 in human cells, and identification of putative modulators. Redox Biol 36:101615. https:\/\/doi.org\/10.1016\/j.redox.2020.101615","journal-title":"Redox Biol"},{"key":"2895_CR52","doi-asserted-by":"publisher","DOI":"10.1016\/j.lana.2021.100046","volume":"2","author":"I Gomes","year":"2021","unstructured":"Gomes I, Karmirian K, Oliveira JT, Pedrosa C, Mendes MA, Rosman FC et al (2021) SARS-CoV-2 infection of the central nervous system in a 14-month-old child: a case report of a complete autopsy. Lancet Reg Health Am 2:100046. https:\/\/doi.org\/10.1016\/j.lana.2021.100046","journal-title":"Lancet Reg Health Am"},{"key":"2895_CR53","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1007\/s00401-024-02743-9","volume":"147","author":"AE Granholm","year":"2024","unstructured":"Granholm AE, Englund E, Gilmore A, Head E, Yong WH, Perez SE et al (2024) Neuropathological findings in down syndrome, Alzheimer\u2019s disease and control patients with and without SARS-COV-2: preliminary findings. Acta Neuropathol 147:92. https:\/\/doi.org\/10.1007\/s00401-024-02743-9","journal-title":"Acta Neuropathol"},{"key":"2895_CR54","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/s41593-024-01576-9","volume":"27","author":"C Greene","year":"2024","unstructured":"Greene C, Connolly R, Brennan D, Laffan A, O\u2019Keeffe E, Zaporojan L et al (2024) Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci 27:421\u2013432. https:\/\/doi.org\/10.1038\/s41593-024-01576-9","journal-title":"Nat Neurosci"},{"key":"2895_CR55","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1093\/hmg\/7.12.1935","volume":"7","author":"C Gunter","year":"1998","unstructured":"Gunter C, Paradee W, Crawford DC, Meadows KA, Newman J, Kunst CB et al (1998) Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1. Hum Mol Genet 7:1935\u20131946. https:\/\/doi.org\/10.1093\/hmg\/7.12.1935","journal-title":"Hum Mol Genet"},{"key":"2895_CR56","doi-asserted-by":"publisher","unstructured":"Gupta T, Kumar M, Kaur UJ, Rao A, Bharti R (2024) Mapping ACE2 and TMPRSS2 co-expression in human brain tissue: implications for SARS-CoV-2 neurological manifestations. J Neurovirol. https:\/\/doi.org\/10.1007\/s13365-024-01206-x","DOI":"10.1007\/s13365-024-01206-x"},{"key":"2895_CR57","doi-asserted-by":"publisher","unstructured":"Gururangan K, Peschansky VJ, Van Hyfte G, Agarwal P, Blank LJ, Mathew B, Goldstein J, Kwon CS, McCarthy L, Cohen A et al (2024) Neuropsychiatric complications of coronavirus disease 2019: Mount Sinai Health System cohort study. J Neurol. https:\/\/doi.org\/10.1007\/s00415-024-12370-9","DOI":"10.1007\/s00415-024-12370-9"},{"key":"2895_CR58","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/s0014-5793(02)03640-2","volume":"532","author":"D Harmer","year":"2002","unstructured":"Harmer D, Gilbert M, Borman R, Clark KL (2002) Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett 532:107\u2013110. https:\/\/doi.org\/10.1016\/s0014-5793(02)03640-2","journal-title":"FEBS Lett"},{"key":"2895_CR59","doi-asserted-by":"publisher","first-page":"2295","DOI":"10.1523\/JNEUROSCI.5107-04.2005","volume":"25","author":"P Helguera","year":"2005","unstructured":"Helguera P, Pelsman A, Pigino G, Wolvetang E, Head E, Busciglio J (2005) ets-2 promotes the activation of a mitochondrial death pathway in down\u2019s syndrome neurons. J Neurosci 25:2295\u20132303. https:\/\/doi.org\/10.1523\/JNEUROSCI.5107-04.2005","journal-title":"J Neurosci"},{"issue":"271\u2013280","key":"2895_CR60","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.052","volume":"181","author":"M Hoffmann","year":"2020","unstructured":"Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S et al (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181(271\u2013280):e278. https:\/\/doi.org\/10.1016\/j.cell.2020.02.052","journal-title":"Cell"},{"key":"2895_CR61","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/BF01534397","volume":"14","author":"MA Horisberger","year":"1988","unstructured":"Horisberger MA, Wathelet M, Szpirer J, Szpirer C, Islam Q, Levan G et al (1988) cDNA cloning and assignment to chromosome 21 of IFI-78K gene, the human equivalent of murine Mx gene. Somat Cell Mol Genet 14:123\u2013131. https:\/\/doi.org\/10.1007\/BF01534397","journal-title":"Somat Cell Mol Genet"},{"key":"2895_CR62","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.100769","volume":"33","author":"A Huls","year":"2021","unstructured":"Huls A, Costa ACS, Dierssen M, Baksh RA, Bargagna S, Baumer NT et al (2021) Medical vulnerability of individuals with down syndrome to severe COVID-19-data from the trisomy 21 research society and the UK ISARIC4C survey. EClinicalMedicine 33:100769. https:\/\/doi.org\/10.1016\/j.eclinm.2021.100769","journal-title":"EClinicalMedicine"},{"issue":"2473\u20132488","key":"2895_CR63","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.10.059","volume":"29","author":"S Hwang","year":"2019","unstructured":"Hwang S, Williams JF, Kneissig M, Lioudyno M, Rivera I, Helguera P et al (2019) Suppressing aneuploidy-associated phenotypes improves the fitness of trisomy 21 cells. Cell Rep 29(2473\u20132488):e2475. https:\/\/doi.org\/10.1016\/j.celrep.2019.10.059","journal-title":"Cell Rep"},{"key":"2895_CR64","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1093\/brain\/awt372","volume":"137","author":"MF Iulita","year":"2014","unstructured":"Iulita MF, Do Carmo S, Ower AK, Fortress AM, Aguilar LF, Hanna M et al (2014) Nerve growth factor metabolic dysfunction in down\u2019s syndrome brains. Brain 137:860\u2013872. https:\/\/doi.org\/10.1093\/brain\/awt372","journal-title":"Brain"},{"key":"2895_CR65","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.12910","volume":"5","author":"MF Iulita","year":"2022","unstructured":"Iulita MF, Garzon Chavez D, Klitgaard Christensen M, Valle Tamayo N, Plana-Ripoll O, Rasmussen SA et al (2022) Association of Alzheimer disease with life expectancy in people with down syndrome. JAMA Netw Open 5:e2212910. https:\/\/doi.org\/10.1001\/jamanetworkopen.2022.12910","journal-title":"JAMA Netw Open"},{"key":"2895_CR66","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","volume":"23","author":"CB Jackson","year":"2022","unstructured":"Jackson CB, Farzan M, Chen B, Choe H (2022) Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 23:3\u201320. https:\/\/doi.org\/10.1038\/s41580-021-00418-x","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2895_CR67","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2024.102474","volume":"79","author":"M Jagst","year":"2024","unstructured":"Jagst M, Pottkamper L, Gomer A, Pitarokoili K, Steinmann E (2024) Neuroinvasion and neurotropism of severe acute respiratory syndrome coronavirus 2 infection. Curr Opin Microbiol 79:102474. https:\/\/doi.org\/10.1016\/j.mib.2024.102474","journal-title":"Curr Opin Microbiol"},{"key":"2895_CR68","doi-asserted-by":"publisher","first-page":"16488","DOI":"10.1038\/s41598-022-20889-y","volume":"12","author":"A Jana","year":"2022","unstructured":"Jana A, Wang X, Leasure JW, Magana L, Wang L, Kim YM et al (2022) Increased type I interferon signaling and brain endothelial barrier dysfunction in an experimental model of Alzheimer\u2019s disease. Sci Rep 12:16488. https:\/\/doi.org\/10.1038\/s41598-022-20889-y","journal-title":"Sci Rep"},{"key":"2895_CR69","doi-asserted-by":"publisher","first-page":"5255","DOI":"10.1523\/JNEUROSCI.0578-19.2019","volume":"39","author":"Y Jiang","year":"2019","unstructured":"Jiang Y, Sato Y, Im E, Berg M, Bordi M, Darji S et al (2019) Lysosomal dysfunction in down syndrome is APP-dependent and mediated by APP-betaCTF (C99). J Neurosci 39:5255\u20135268. https:\/\/doi.org\/10.1523\/JNEUROSCI.0578-19.2019","journal-title":"J Neurosci"},{"key":"2895_CR70","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/s41392-021-00591-7","volume":"6","author":"L Jiao","year":"2021","unstructured":"Jiao L, Yang Y, Yu W, Zhao Y, Long H, Gao J et al (2021) The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys. Signal Transduct Target Ther 6:169. https:\/\/doi.org\/10.1038\/s41392-021-00591-7","journal-title":"Signal Transduct Target Ther"},{"key":"2895_CR71","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2023.114379","volume":"363","author":"Y Kase","year":"2023","unstructured":"Kase Y, Sonn I, Goto M, Murakami R, Sato T, Okano H (2023) The original strain of SARS-CoV-2, the Delta variant, and the Omicron variant infect microglia efficiently, in contrast to their inability to infect neurons: analysis using 2D and 3D cultures. Exp Neurol 363:114379. https:\/\/doi.org\/10.1016\/j.expneurol.2023.114379","journal-title":"Exp Neurol"},{"key":"2895_CR72","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1177\/10738584231194927","volume":"30","author":"D Kempuraj","year":"2024","unstructured":"Kempuraj D, Aenlle KK, Cohen J, Mathew A, Isler D, Pangeni RP et al (2024) COVID-19 and long COVID: disruption of the neurovascular unit, blood-brain barrier, and tight junctions. Neuroscientist 30:421\u2013439. https:\/\/doi.org\/10.1177\/10738584231194927","journal-title":"Neuroscientist"},{"key":"2895_CR73","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/s0736-5748(99)00036-2","volume":"17","author":"DM Kerkovich","year":"1999","unstructured":"Kerkovich DM, Sapp D, Weidenheim K, Brosnan CF, Pfeiffer SE, Yeh HH et al (1999) Fetal human cortical neurons grown in culture: morphological differentiation, biochemical correlates and development of electrical activity. Int J Dev Neurosci 17:347\u2013356. https:\/\/doi.org\/10.1016\/s0736-5748(99)00036-2","journal-title":"Int J Dev Neurosci"},{"key":"2895_CR74","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2023.105570","volume":"169","author":"SR Kim","year":"2023","unstructured":"Kim SR, Eom Y, Lee SH (2023) Comprehensive analysis of sex differences in the function and ultrastructure of hippocampal presynaptic terminals. Neurochem Int 169:105570. https:\/\/doi.org\/10.1016\/j.neuint.2023.105570","journal-title":"Neurochem Int"},{"key":"2895_CR75","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021107821","volume":"40","author":"J Koch","year":"2021","unstructured":"Koch J, Uckeley ZM, Doldan P, Stanifer M, Boulant S, Lozach PY (2021) TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells. EMBO J 40:e107821. https:\/\/doi.org\/10.15252\/embj.2021107821","journal-title":"EMBO J"},{"key":"2895_CR76","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1007\/s10875-020-00803-9","volume":"40","author":"XF Kong","year":"2020","unstructured":"Kong XF, Worley L, Rinchai D, Bondet V, Jithesh PV, Goulet M et al (2020) Three copies of four interferon receptor genes underlie a mild type I interferonopathy in down syndrome. J Clin Immunol 40:807\u2013819. https:\/\/doi.org\/10.1007\/s10875-020-00803-9","journal-title":"J Clin Immunol"},{"key":"2895_CR77","first-page":"236","volume":"47","author":"JR Korenberg","year":"1990","unstructured":"Korenberg JR, Kawashima H, Pulst SM, Ikeuchi T, Ogasawara N, Yamamoto K et al (1990) Molecular definition of a region of chromosome 21 that causes features of the down syndrome phenotype. Am J Hum Genet 47:236\u2013246","journal-title":"Am J Hum Genet"},{"key":"2895_CR78","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.stemcr.2021.12.011","volume":"17","author":"S Krasemann","year":"2022","unstructured":"Krasemann S, Haferkamp U, Pfefferle S, Woo MS, Heinrich F, Schweizer M et al (2022) The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Reports 17:307\u2013320. https:\/\/doi.org\/10.1016\/j.stemcr.2021.12.011","journal-title":"Stem Cell Reports"},{"key":"2895_CR79","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s40478-023-01566-1","volume":"11","author":"L Lebrun","year":"2023","unstructured":"Lebrun L, Absil L, Remmelink M, De Mendonca R, D\u2019Haene N, Gaspard N et al (2023) SARS-Cov-2 infection and neuropathological findings: a report of 18 cases and review of the literature. Acta Neuropathol Commun 11:78. https:\/\/doi.org\/10.1186\/s40478-023-01566-1","journal-title":"Acta Neuropathol Commun"},{"key":"2895_CR80","doi-asserted-by":"publisher","first-page":"2061","DOI":"10.3389\/fimmu.2018.02061","volume":"9","author":"AJ Lee","year":"2018","unstructured":"Lee AJ, Ashkar AA (2018) The dual nature of type I and type II interferons. Front Immunol 9:2061. https:\/\/doi.org\/10.3389\/fimmu.2018.02061","journal-title":"Front Immunol"},{"key":"2895_CR81","doi-asserted-by":"publisher","unstructured":"Leng A, Shah M, Ahmad SA, Premraj L, Wildi K, Li Bassi G, Pardo CA, Choi A, Cho SM (2023) Pathogenesis underlying neurological manifestations of long COVID syndrome and potential therapeutics. Cells 12. https:\/\/doi.org\/10.3390\/cells12050816","DOI":"10.3390\/cells12050816"},{"key":"2895_CR82","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/s10571-020-00947-7","volume":"42","author":"WJ Lukiw","year":"2022","unstructured":"Lukiw WJ, Pogue A, Hill JM (2022) SARS-CoV-2 infectivity and neurological targets in the brain. Cell Mol Neurobiol 42:217\u2013224. https:\/\/doi.org\/10.1007\/s10571-020-00947-7","journal-title":"Cell Mol Neurobiol"},{"issue":"2074\u20132084","key":"2895_CR83","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.09.007","volume":"55","author":"L Malle","year":"2022","unstructured":"Malle L, Martin-Fernandez M, Buta S, Richardson A, Bush D, Bogunovic D (2022) Excessive negative regulation of type I interferon disrupts viral control in individuals with down syndrome. Immunity 55(2074\u20132084):e2075. https:\/\/doi.org\/10.1016\/j.immuni.2022.09.007","journal-title":"Immunity"},{"key":"2895_CR84","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1001\/jamaneurol.2020.1127","volume":"77","author":"L Mao","year":"2020","unstructured":"Mao L, Jin H, Wang M, Hu Y, Chen S, He Q et al (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 77:683\u2013690. https:\/\/doi.org\/10.1001\/jamaneurol.2020.1127","journal-title":"JAMA Neurol"},{"key":"2895_CR85","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1016\/j.neuron.2022.04.001","volume":"110","author":"AC Martini","year":"2022","unstructured":"Martini AC, Gross TJ, Head E, Mapstone M (2022) Beyond amyloid: Immune, cerebrovascular, and metabolic contributions to Alzheimer disease in people with down syndrome. Neuron 110:2063\u20132079. https:\/\/doi.org\/10.1016\/j.neuron.2022.04.001","journal-title":"Neuron"},{"key":"2895_CR86","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/S1474-4422(20)30308-2","volume":"19","author":"J Matschke","year":"2020","unstructured":"Matschke J, Lutgehetmann M, Hagel C, Sperhake JP, Schroder AS, Edler C et al (2020) Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol 19:919\u2013929. https:\/\/doi.org\/10.1016\/S1474-4422(20)30308-2","journal-title":"Lancet Neurol"},{"key":"2895_CR87","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/s41593-020-00758-5","volume":"24","author":"J Meinhardt","year":"2021","unstructured":"Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R et al (2021) Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 24:168\u2013175. https:\/\/doi.org\/10.1038\/s41593-020-00758-5","journal-title":"Nat Neurosci"},{"key":"2895_CR88","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/s41583-023-00769-8","volume":"25","author":"J Meinhardt","year":"2024","unstructured":"Meinhardt J, Streit S, Dittmayer C, Manitius RV, Radbruch H, Heppner FL (2024) The neurobiology of SARS-CoV-2 infection. Nat Rev Neurosci 25:30\u201342. https:\/\/doi.org\/10.1038\/s41583-023-00769-8","journal-title":"Nat Rev Neurosci"},{"key":"2895_CR89","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1111\/his.14134","volume":"77","author":"T Menter","year":"2020","unstructured":"Menter T, Haslbauer JD, Nienhold R, Savic S, Hopfer H, Deigendesch N et al (2020) Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology 77:198\u2013209. https:\/\/doi.org\/10.1111\/his.14134","journal-title":"Histopathology"},{"key":"2895_CR90","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1038\/s41588-020-00732-8","volume":"52","author":"KW Ng","year":"2020","unstructured":"Ng KW, Attig J, Bolland W, Young GR, Major J, Wrobel AG et al (2020) Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option. Nat Genet 52:1294\u20131302. https:\/\/doi.org\/10.1038\/s41588-020-00732-8","journal-title":"Nat Genet"},{"key":"2895_CR91","doi-asserted-by":"publisher","first-page":"4459","DOI":"10.7150\/thno.72676","volume":"12","author":"N Noren Hooten","year":"2022","unstructured":"Noren Hooten N, Byappanahalli AM, Vannoy M, Omoniyi V, Evans MK (2022) Influences of age, race, and sex on extracellular vesicle characteristics. Theranostics 12:4459\u20134476. https:\/\/doi.org\/10.7150\/thno.72676","journal-title":"Theranostics"},{"key":"2895_CR92","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1007\/s13760-023-02291-1","volume":"123","author":"A Nouraeinejad","year":"2023","unstructured":"Nouraeinejad A (2023) The functional and structural changes in the hippocampus of COVID-19 patients. Acta Neurol Belg 123:1247\u20131256. https:\/\/doi.org\/10.1007\/s13760-023-02291-1","journal-title":"Acta Neurol Belg"},{"key":"2895_CR93","doi-asserted-by":"publisher","DOI":"10.1016\/j.anndiagpath.2022.152057","volume":"61","author":"GJ Nuovo","year":"2022","unstructured":"Nuovo GJ, Suster D, Sawant D, Mishra A, Michaille JJ, Tili E (2022) The amplification of CNS damage in Alzheimer\u2019s disease due to SARS-CoV2 infection. Ann Diagn Pathol 61:152057. https:\/\/doi.org\/10.1016\/j.anndiagpath.2022.152057","journal-title":"Ann Diagn Pathol"},{"key":"2895_CR94","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/652817","volume":"2014","author":"S Olivan","year":"2014","unstructured":"Olivan S, Calvo AC, Manzano R, Zaragoza P, Osta R (2014) Sex differences in constitutive autophagy. Biomed Res Int 2014:652817. https:\/\/doi.org\/10.1155\/2014\/652817","journal-title":"Biomed Res Int"},{"key":"2895_CR95","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01969-21","volume":"96","author":"GM Olivarria","year":"2022","unstructured":"Olivarria GM, Cheng Y, Furman S, Pachow C, Hohsfield LA, Smith-Geater C et al (2022) Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-human ACE2 transgenic mice. J Virol 96:e0196921. https:\/\/doi.org\/10.1128\/jvi.01969-21","journal-title":"J Virol"},{"key":"2895_CR96","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1038\/s41588-020-00731-9","volume":"52","author":"OO Onabajo","year":"2020","unstructured":"Onabajo OO, Banday AR, Stanifer ML, Yan W, Obajemu A, Santer DM et al (2020) Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor. Nat Genet 52:1283\u20131293. https:\/\/doi.org\/10.1038\/s41588-020-00731-9","journal-title":"Nat Genet"},{"key":"2895_CR97","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.14726","volume":"9","author":"L Ostergaard","year":"2021","unstructured":"Ostergaard L (2021) SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: consequences of capillary transit-time changes, tissue hypoxia and inflammation. Physiol Rep 9:e14726. https:\/\/doi.org\/10.14814\/phy2.14726","journal-title":"Physiol Rep"},{"key":"2895_CR98","doi-asserted-by":"publisher","first-page":"245","DOI":"10.3389\/fnagi.2018.00245","volume":"10","author":"BR Ott","year":"2018","unstructured":"Ott BR, Jones RN, Daiello LA, de la Monte SM, Stopa EG, Johanson CE et al (2018) Blood-cerebrospinal fluid barrier gradients in mild cognitive impairment and Alzheimer\u2019s disease: relationship to inflammatory cytokines and chemokines. Front Aging Neurosci 10:245. https:\/\/doi.org\/10.3389\/fnagi.2018.00245","journal-title":"Front Aging Neurosci"},{"key":"2895_CR99","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009212","volume":"17","author":"T Ou","year":"2021","unstructured":"Ou T, Mou H, Zhang L, Ojha A, Choe H, Farzan M (2021) Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2. PLoS Pathog 17:e1009212. https:\/\/doi.org\/10.1371\/journal.ppat.1009212","journal-title":"PLoS Pathog"},{"key":"2895_CR100","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1002\/jmv.25915","volume":"92","author":"A Paniz-Mondolfi","year":"2020","unstructured":"Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J et al (2020) Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol 92:699\u2013702. https:\/\/doi.org\/10.1002\/jmv.25915","journal-title":"J Med Virol"},{"key":"2895_CR101","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1006\/geno.1997.4845","volume":"44","author":"A Paoloni-Giacobino","year":"1997","unstructured":"Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE (1997) Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3. Genomics 44:309\u2013320. https:\/\/doi.org\/10.1006\/geno.1997.4845","journal-title":"Genomics"},{"key":"2895_CR102","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.mad.2011.10.001","volume":"133","author":"D Patterson","year":"2012","unstructured":"Patterson D, Cabelof DC (2012) Down syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging. Mech Ageing Dev 133:133\u2013137. https:\/\/doi.org\/10.1016\/j.mad.2011.10.001","journal-title":"Mech Ageing Dev"},{"key":"2895_CR103","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/s0736-5748(03)00031-5","volume":"21","author":"A Pelsman","year":"2003","unstructured":"Pelsman A, Hoyo-Vadillo C, Gudasheva TA, Seredenin SB, Ostrovskaya RU, Busciglio J (2003) GVS-111 prevents oxidative damage and apoptosis in normal and down\u2019s syndrome human cortical neurons. Int J Dev Neurosci 21:117\u2013124. https:\/\/doi.org\/10.1016\/s0736-5748(03)00031-5","journal-title":"Int J Dev Neurosci"},{"key":"2895_CR104","doi-asserted-by":"publisher","DOI":"10.1002\/iid3.1219","volume":"12","author":"PNK Pitchan Velammal","year":"2024","unstructured":"Pitchan Velammal PNK, Balasubramanian S, Ayoobkhan FS, Mohan GVK, Aggarwal P, Rabaan AA et al (2024) COVID-19 in patients with down syndrome: a systematic review. Immun Inflamm Dis 12:e1219. https:\/\/doi.org\/10.1002\/iid3.1219","journal-title":"Immun Inflamm Dis"},{"key":"2895_CR105","doi-asserted-by":"publisher","first-page":"4766","DOI":"10.1038\/s41467-019-12739-9","volume":"10","author":"RK Powers","year":"2019","unstructured":"Powers RK, Culp-Hill R, Ludwig MP, Smith KP, Waugh KA, Minter R et al (2019) Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors. Nat Commun 10:4766. https:\/\/doi.org\/10.1038\/s41467-019-12739-9","journal-title":"Nat Commun"},{"key":"2895_CR106","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1056\/NEJMc2011400","volume":"383","author":"VG Puelles","year":"2020","unstructured":"Puelles VG, Lutgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L et al (2020) Multiorgan and renal tropism of SARS-CoV-2. N Engl J Med 383:590\u2013592. https:\/\/doi.org\/10.1056\/NEJMc2011400","journal-title":"N Engl J Med"},{"key":"2895_CR107","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.986840","volume":"13","author":"M Pujantell","year":"2022","unstructured":"Pujantell M, Altfeld M (2022) Consequences of sex differences in type I IFN responses for the regulation of antiviral immunity. Front Immunol 13:986840. https:\/\/doi.org\/10.3389\/fimmu.2022.986840","journal-title":"Front Immunol"},{"key":"2895_CR108","doi-asserted-by":"publisher","unstructured":"Qi J, Zhou Y, Hua J, Zhang L, Bian J, Liu B, Zhao Z, Jin S (2021) The scRNA-seq expression profiling of the receptor ACE2 and the cellular protease TMPRSS2 reveals human organs susceptible to SARS-CoV-2 infection. Int J Environ Res Public Health 18. https:\/\/doi.org\/10.3390\/ijerph18010284","DOI":"10.3390\/ijerph18010284"},{"key":"2895_CR109","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2407437121","volume":"121","author":"B Qu","year":"2024","unstructured":"Qu B, Miskey C, Gomer A, Kleinert RDV, Ibanez SC, Eberle R et al (2024) TMPRSS2-mediated SARS-CoV-2 uptake boosts innate immune activation, enhances cytopathology, and drives convergent virus evolution. Proc Natl Acad Sci USA 121:e2407437121. https:\/\/doi.org\/10.1073\/pnas.2407437121","journal-title":"Proc Natl Acad Sci USA"},{"key":"2895_CR110","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1186\/s40478-023-01647-1","volume":"11","author":"L Reveret","year":"2023","unstructured":"Reveret L, Leclerc M, Emond V, Tremblay C, Loiselle A, Bourassa P et al (2023) Higher angiotensin-converting enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer\u2019s disease. Acta Neuropathol Commun 11:159. https:\/\/doi.org\/10.1186\/s40478-023-01647-1","journal-title":"Acta Neuropathol Commun"},{"key":"2895_CR111","doi-asserted-by":"publisher","unstructured":"Sacchi A, Giannessi F, Sabatini A, Percario ZA, Affabris E (2023) SARS-CoV-2 evasion of the interferon system: can we restore its effectiveness? Int J Mol Sci 24. https:\/\/doi.org\/10.3390\/ijms24119353","DOI":"10.3390\/ijms24119353"},{"key":"2895_CR112","doi-asserted-by":"publisher","unstructured":"Schubert C, Allhoff M, Tillmann S, Maie T, Costa IG, Lipka DB, Schemionek M, Feldberg K, Baumeister J, Brummendorf THet al (2019) Differential roles of STAT1 and STAT2 in the sensitivity of JAK2V617F- vs. BCR-ABL-positive cells to interferon alpha. J Hematol Oncol 12:36. https:\/\/doi.org\/10.1186\/s13045-019-0722-9","DOI":"10.1186\/s13045-019-0722-9"},{"key":"2895_CR113","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1093\/jnen\/nlac056","volume":"81","author":"GE Serrano","year":"2022","unstructured":"Serrano GE, Walker JE, Tremblay C, Piras IS, Huentelman MJ, Belden CM et al (2022) SARS-CoV-2 brain regional detection, histopathology, gene expression, and immunomodulatory changes in decedents with COVID-19. J Neuropathol Exp Neurol 81:666\u2013695. https:\/\/doi.org\/10.1093\/jnen\/nlac056","journal-title":"J Neuropathol Exp Neurol"},{"key":"2895_CR114","doi-asserted-by":"publisher","first-page":"11876","DOI":"10.1073\/pnas.0505577102","volume":"102","author":"G Simmons","year":"2005","unstructured":"Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P (2005) Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci USA 102:11876\u201311881. https:\/\/doi.org\/10.1073\/pnas.0505577102","journal-title":"Proc Natl Acad Sci USA"},{"key":"2895_CR115","doi-asserted-by":"publisher","unstructured":"Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Yet al (2021) Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exp Med 218. https:\/\/doi.org\/10.1084\/jem.20202135","DOI":"10.1084\/jem.20202135"},{"key":"2895_CR116","doi-asserted-by":"publisher","first-page":"834","DOI":"10.3390\/v5030834","volume":"5","author":"F Sorgeloos","year":"2013","unstructured":"Sorgeloos F, Kreit M, Hermant P, Lardinois C, Michiels T (2013) Antiviral type I and type III interferon responses in the central nervous system. Viruses 5:834\u2013857. https:\/\/doi.org\/10.3390\/v5030834","journal-title":"Viruses"},{"key":"2895_CR117","doi-asserted-by":"publisher","first-page":"4193","DOI":"10.1093\/brain\/awac270","volume":"145","author":"AL Soung","year":"2022","unstructured":"Soung AL, Vanderheiden A, Nordvig AS, Sissoko CA, Canoll P, Mariani MB et al (2022) COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis. Brain 145:4193\u20134201. https:\/\/doi.org\/10.1093\/brain\/awac270","journal-title":"Brain"},{"key":"2895_CR118","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104558","volume":"91","author":"I Spera","year":"2023","unstructured":"Spera I, Cousin N, Ries M, Kedracka A, Castillo A, Aleandri S et al (2023) Open pathways for cerebrospinal fluid outflow at the cribriform plate along the olfactory nerves. EBioMedicine 91:104558. https:\/\/doi.org\/10.1016\/j.ebiom.2023.104558","journal-title":"EBioMedicine"},{"key":"2895_CR119","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1038\/s41586-022-05542-y","volume":"612","author":"SR Stein","year":"2022","unstructured":"Stein SR, Ramelli SC, Grazioli A, Chung JY, Singh M, Yinda CK et al (2022) SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature 612:758\u2013763. https:\/\/doi.org\/10.1038\/s41586-022-05542-y","journal-title":"Nature"},{"key":"2895_CR120","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002097","volume":"21","author":"MS Strine","year":"2023","unstructured":"Strine MS, Cai WL, Wei J, Alfajaro MM, Filler RB, Biering SB et al (2023) DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner. PLoS Biol 21:e3002097. https:\/\/doi.org\/10.1371\/journal.pbio.3002097","journal-title":"PLoS Biol"},{"key":"2895_CR121","doi-asserted-by":"publisher","unstructured":"Subramaniyan B, Larabee JL, Bodas M, Moore AR, Burgett AWG, Myers DA, Georgescu C, Wren JD, Papin JF, Walters MS (2021) Characterization of the SARS-CoV-2 host response in primary human airway epithelial cells from aged individuals. Viruses 13. https:\/\/doi.org\/10.3390\/v13081603","DOI":"10.3390\/v13081603"},{"key":"2895_CR122","doi-asserted-by":"publisher","unstructured":"Sullivan KD, Lewis HC, Hill AA, Pandey A, Jackson LP, Cabral JM, Smith KP, Liggett LA, Gomez EB, Galbraith MD et al (2016) Trisomy 21 consistently activates the interferon response. Elife 5. https:\/\/doi.org\/10.7554\/eLife.16220","DOI":"10.7554\/eLife.16220"},{"key":"2895_CR123","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1038\/s41590-022-01152-y","volume":"23","author":"TS Sumida","year":"2022","unstructured":"Sumida TS, Dulberg S, Schupp JC, Lincoln MR, Stillwell HA, Axisa PP et al (2022) Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells. Nat Immunol 23:632\u2013642. https:\/\/doi.org\/10.1038\/s41590-022-01152-y","journal-title":"Nat Immunol"},{"key":"2895_CR124","doi-asserted-by":"publisher","first-page":"2696","DOI":"10.1093\/brain\/awab148","volume":"144","author":"KT Thakur","year":"2021","unstructured":"Thakur KT, Miller EH, Glendinning MD, Al-Dalahmah O, Banu MA, Boehme AK et al (2021) COVID-19 neuropathology at Columbia University Irving Medical Center\/New York Presbyterian Hospital. Brain 144:2696\u20132708. https:\/\/doi.org\/10.1093\/brain\/awab148","journal-title":"Brain"},{"key":"2895_CR125","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.stemcr.2021.02.005","volume":"16","author":"SK Tiwari","year":"2021","unstructured":"Tiwari SK, Wang S, Smith D, Carlin AF, Rana TM (2021) Revealing tissue-specific SARS-CoV-2 infection and host responses using human stem cell-derived lung and cerebral organoids. Stem Cell Reports 16:437\u2013445. https:\/\/doi.org\/10.1016\/j.stemcr.2021.02.005","journal-title":"Stem Cell Reports"},{"key":"2895_CR126","doi-asserted-by":"publisher","unstructured":"Tolomeo M, Cavalli A, Cascio A (2022) STAT1 and its crucial role in the control of viral infections. Int J Mol Sci 23. https:\/\/doi.org\/10.3390\/ijms23084095","DOI":"10.3390\/ijms23084095"},{"key":"2895_CR127","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/0014-5793(91)80804-c","volume":"285","author":"V Turk","year":"1991","unstructured":"Turk V, Bode W (1991) The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett 285:213\u2013219. https:\/\/doi.org\/10.1016\/0014-5793(91)80804-c","journal-title":"FEBS Lett"},{"key":"2895_CR128","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.614680","volume":"14","author":"P Varma","year":"2020","unstructured":"Varma P, Lybrand ZR, Antopia MC, Hsieh J (2020) Novel targets of SARS-CoV-2 spike protein in human fetal brain development suggest early pregnancy vulnerability. Front Neurosci 14:614680. https:\/\/doi.org\/10.3389\/fnins.2020.614680","journal-title":"Front Neurosci"},{"key":"2895_CR129","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s00221-021-06244-z","volume":"240","author":"S Veleri","year":"2022","unstructured":"Veleri S (2022) Neurotropism of SARS-CoV-2 and neurological diseases of the central nervous system in COVID-19 patients. Exp Brain Res 240:9\u201325. https:\/\/doi.org\/10.1007\/s00221-021-06244-z","journal-title":"Exp Brain Res"},{"key":"2895_CR130","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1186\/1471-2164-12-229","volume":"12","author":"M Vilardell","year":"2011","unstructured":"Vilardell M, Rasche A, Thormann A, Maschke-Dutz E, Perez-Jurado LA, Lehrach H et al (2011) Meta-analysis of heterogeneous down syndrome data reveals consistent genome-wide dosage effects related to neurological processes. BMC Genomics 12:229. https:\/\/doi.org\/10.1186\/1471-2164-12-229","journal-title":"BMC Genomics"},{"key":"2895_CR131","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1021\/bi00653a012","volume":"15","author":"LP Villarreal","year":"1976","unstructured":"Villarreal LP, Breindl M, Holland JJ (1976) Determination of molar ratios of vesicular stomatitis virus induced RNA species in BHK21 cells. Biochemistry 15:1663\u20131667. https:\/\/doi.org\/10.1021\/bi00653a012","journal-title":"Biochemistry"},{"key":"2895_CR132","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/cr.2008.15","volume":"18","author":"H Wang","year":"2008","unstructured":"Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G et al (2008) SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res 18:290\u2013301. https:\/\/doi.org\/10.1038\/cr.2008.15","journal-title":"Cell Res"},{"key":"2895_CR133","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.7150\/ijms.46695","volume":"17","author":"Y Wang","year":"2020","unstructured":"Wang Y, Wang Y, Luo W, Huang L, Xiao J, Li F et al (2020) A comprehensive investigation of the mRNA and protein level of ACE2, the putative receptor of SARS-CoV-2, in human tissues and blood cells. Int J Med Sci 17:1522\u20131531. https:\/\/doi.org\/10.7150\/ijms.46695","journal-title":"Int J Med Sci"},{"key":"2895_CR134","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1038\/s41588-023-01399-7","volume":"55","author":"KA Waugh","year":"2023","unstructured":"Waugh KA, Minter R, Baxter J, Chi C, Galbraith MD, Tuttle KD et al (2023) Triplication of the interferon receptor locus contributes to hallmarks of down syndrome in a mouse model. Nat Genet 55:1034\u20131047. https:\/\/doi.org\/10.1038\/s41588-023-01399-7","journal-title":"Nat Genet"},{"key":"2895_CR135","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s40478-021-01300-9","volume":"10","author":"J Wegiel","year":"2022","unstructured":"Wegiel J, Flory M, Kuchna I, Nowicki K, Ma SY, Zhong N et al (2022) Developmental deficits and staging of dynamics of age associated Alzheimer\u2019s disease neurodegeneration and neuronal loss in subjects with Down syndrome. Acta Neuropathol Commun 10:2. https:\/\/doi.org\/10.1186\/s40478-021-01300-9","journal-title":"Acta Neuropathol Commun"},{"key":"2895_CR136","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s40478-021-01300-9","volume":"10","author":"J Wegiel","year":"2022","unstructured":"Wegiel J, Flory M, Kuchna I, Nowicki K, Wegiel J, Ma SY et al (2022) Developmental deficits and staging of dynamics of age associated Alzheimer\u2019s disease neurodegeneration and neuronal loss in subjects with Down syndrome. Acta Neuropathol Commun 10:2. https:\/\/doi.org\/10.1186\/s40478-021-01300-9","journal-title":"Acta Neuropathol Commun"},{"key":"2895_CR137","doi-asserted-by":"publisher","first-page":"7642","DOI":"10.1128\/jvi.76.15.7642-7650.2002","volume":"76","author":"GW Wertz","year":"2002","unstructured":"Wertz GW, Moudy R, Ball LA (2002) Adding genes to the RNA genome of vesicular stomatitis virus: positional effects on stability of expression. J Virol 76:7642\u20137650. https:\/\/doi.org\/10.1128\/jvi.76.15.7642-7650.2002","journal-title":"J Virol"},{"key":"2895_CR138","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/s0969-9961(03)00107-4","volume":"14","author":"EJ Wolvetang","year":"2003","unstructured":"Wolvetang EJ, Bradfield OM, Hatzistavrou T, Crack PJ, Busciglio J, Kola I et al (2003) Overexpression of the chromosome 21 transcription factor Ets2 induces neuronal apoptosis. Neurobiol Dis 14:349\u2013356. https:\/\/doi.org\/10.1016\/s0969-9961(03)00107-4","journal-title":"Neurobiol Dis"},{"key":"2895_CR139","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s40478-023-01632-8","volume":"11","author":"Y Wu","year":"2023","unstructured":"Wu Y, Mumford P, Noy S, Cleverley K, Mrzyglod A, Luo D et al (2023) Cathepsin B abundance, activity and microglial localisation in Alzheimer\u2019s disease-down syndrome and early onset Alzheimer\u2019s disease; the role of elevated cystatin B. Acta Neuropathol Commun 11:132. https:\/\/doi.org\/10.1186\/s40478-023-01632-8","journal-title":"Acta Neuropathol Commun"},{"key":"2895_CR140","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108234","volume":"33","author":"H Xia","year":"2020","unstructured":"Xia H, Cao Z, Xie X, Zhang X, Chen JY, Wang H et al (2020) Evasion of type I interferon by SARS-CoV-2. Cell Rep 33:108234. https:\/\/doi.org\/10.1016\/j.celrep.2020.108234","journal-title":"Cell Rep"},{"key":"2895_CR141","doi-asserted-by":"publisher","unstructured":"Xu D, Qin X (2024) Type I Interferonopathy among non-elderly female patients with post-acute sequelae of COVID-19. Viruses 16. https:\/\/doi.org\/10.3390\/v16091369","DOI":"10.3390\/v16091369"},{"key":"2895_CR142","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13182","volume":"19","author":"N Yanguas-Casas","year":"2020","unstructured":"Yanguas-Casas N, Crespo-Castrillo A, Arevalo MA, Garcia-Segura LM (2020) Aging and sex: impact on microglia phagocytosis. Aging Cell 19:e13182. https:\/\/doi.org\/10.1111\/acel.13182","journal-title":"Aging Cell"},{"key":"2895_CR143","doi-asserted-by":"publisher","first-page":"6208","DOI":"10.1038\/s41467-021-26270-3","volume":"12","author":"M Yeo","year":"2021","unstructured":"Yeo M, Chen Y, Jiang C, Chen G, Wang K, Chandra S et al (2021) Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission. Nat Commun 12:6208. https:\/\/doi.org\/10.1038\/s41467-021-26270-3","journal-title":"Nat Commun"},{"key":"2895_CR144","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1111\/gtc.12316","volume":"21","author":"K Yuasa","year":"2016","unstructured":"Yuasa K, Hijikata T (2016) Distal regulatory element of the STAT1 gene potentially mediates positive feedback control of STAT1 expression. Genes Cells 21:25\u201340. https:\/\/doi.org\/10.1111\/gtc.12316","journal-title":"Genes Cells"},{"key":"2895_CR145","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12812","volume":"17","author":"E Zamponi","year":"2018","unstructured":"Zamponi E, Zamponi N, Coskun P, Quassollo G, Lorenzo A, Cannas SA et al (2018) Nrf2 stabilization prevents critical oxidative damage in down syndrome cells. Aging Cell 17:e12812. https:\/\/doi.org\/10.1111\/acel.12812","journal-title":"Aging Cell"},{"key":"2895_CR146","doi-asserted-by":"publisher","first-page":"232","DOI":"10.5114\/fn.2021.109495","volume":"59","author":"Y Zhao","year":"2021","unstructured":"Zhao Y, Li W, Lukiw W (2021) Ubiquity of the SARS-CoV-2 receptor ACE2 and upregulation in limbic regions of Alzheimer\u2019s disease brain. Folia Neuropathol 59:232\u2013238. https:\/\/doi.org\/10.5114\/fn.2021.109495","journal-title":"Folia Neuropathol"},{"key":"2895_CR147","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1002\/ddrr.1128","volume":"18","author":"WB Zigman","year":"2013","unstructured":"Zigman WB (2013) Atypical aging in down syndrome. Dev Disabil Res Rev 18:51\u201367. https:\/\/doi.org\/10.1002\/ddrr.1128","journal-title":"Dev Disabil Res Rev"}],"container-title":["Acta Neuropathologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02895-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00401-025-02895-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00401-025-02895-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T05:17:42Z","timestamp":1748582262000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00401-025-02895-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,30]]},"references-count":147,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["2895"],"URL":"https:\/\/doi.org\/10.1007\/s00401-025-02895-2","relation":{},"ISSN":["1432-0533"],"issn-type":[{"value":"1432-0533","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,30]]},"assertion":[{"value":"10 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Conflict of interest J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche, Zamb\u00f3n and outside the submitted work. J.F. reports holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to ADx, EPI8382175.0). Other authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"54"}}